The overall number of people living with HIV-1 has continued to increase in all regions of the world. With no prospect for an effective vaccine, containment of the spread of HIV-1 relies on measures to prevent transmission, and treatment relies on antiretroviral therapy. However, drug resistance is becoming increasingly problematic, with some individuals harboring and transmitting viruses that are resistant to a number of different drugs. Thus, an increasing number of people are left with little or no options for new therapeutics. This highlights the need for the development of new antiretroviral agents. We recently discovered that a small molecule of Streptococcus cristatus CC5A (S. cristatus CC5A) is able to up-regulate APOBEC3G and APOBEC3F expression and inhibit HIV replication. The specific effort of this proposal is to characterize this small molecule and to examine the clinical potential of the small molecule in development of novel anti-HIV drug. We hypothesize that the small molecule of S. cristatus CC5A enhances innate immunity through up- regulating APOBEC3G and APOBEC3F expression and could be a potential novel anti-HIV drug candidate. To test the hypothesis, we propose following specific aims. (1) To identify and characterize the small molecule of S. cristatus CC5A that promotes A3F and A3G expression. (2) To exploit the possibility of S. cristatus upregulating APOBEC3 and inhibiting HIV replication or transmission in primary HIV target cells, including CD4+ T-cells, macrophages and dendritic cells. (3) To elucidate the mechanism by which the small molecule activates APOBEC3 gene transcription. The successful completion of the proposal will lay the groundwork for developing the small molecule to a novel anti-HIV drug. PUBLIC HEALTH RELEVANCE: Human immunodeficiency virus (HIV) is the causative agent of AIDS, a devastating pandemic disease with a 2007 estimate of 33.2 million people infected and around 2 million dead. The goal of this proposal is to characterize a small molecule from non-pathogenic oral bacteria that can inhibit HIV replication. This study will yield valuable information for developing novel anti-AIDS drug, eventually providing new weapons to fight HIV/AIDS.